U.S. patent application number 10/832174 was filed with the patent office on 2005-10-27 for topical treatment of acne, seborrheic dermatitis, and oily skin with formulations containing histamine antagonists.
Invention is credited to McCook, John P., Stephens, Thomas J..
Application Number | 20050238597 10/832174 |
Document ID | / |
Family ID | 35136677 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050238597 |
Kind Code |
A1 |
McCook, John P. ; et
al. |
October 27, 2005 |
Topical treatment of acne, seborrheic dermatitis, and oily skin
with formulations containing histamine antagonists
Abstract
Topical compositions containing histamine antagonists together
with pharmaceutically acceptable salts and dermatological
acceptable carrier vehicles are applied to the skin of human
patients to inhibit sebaceous gland activity associated with acne,
seborrheic dermatitis (seborrhea), and cosmetic oily skin
conditions.
Inventors: |
McCook, John P.; (Frisco,
TX) ; Stephens, Thomas J.; (Plano, TX) |
Correspondence
Address: |
THEODORE C. JAY
16 NORTH CHATSWORTH AVE.
APARTMENT 600
LARCHMONT
NY
10538
US
|
Family ID: |
35136677 |
Appl. No.: |
10/832174 |
Filed: |
April 26, 2004 |
Current U.S.
Class: |
424/66 |
Current CPC
Class: |
A61Q 19/00 20130101;
A61K 8/4926 20130101; A61Q 19/008 20130101; A61K 8/4953 20130101;
A61K 8/494 20130101; A61K 8/49 20130101; A61K 8/41 20130101 |
Class at
Publication: |
424/066 |
International
Class: |
A61K 007/135 |
Claims
What is claimed is:
1. A method of reducing sebaceous gland activity in the skin of a
human patient susceptible to having excessive or abnormal sebaceous
gland activity which comprises the step of administering to said
skin a topical composition consisting essentially of: (a) a safe
and effective amount of at least one material selected from the
class of histamine antagonists and pharmaceutically-acceptable
salts thereof, and (b) a dermatological-acceptable carrier
vehicle.
2. The method of claim 1 wherein the subsequent treatment of one or
more of the conditions of acne, seborrhea, and seborrheic
dermatitis is enhanced as compared to said treatment lacking such
administration.
3. The method of claim 1 wherein the patient has oily or
combination of oily to dry skin,
4. The method of claim 3 wherein the skin is associated with large
pores, closed or open comedones and or fine lines or wrinkles.
5. A composition which when applied to the skin of a human patient
susceptible to having excessive or abnormal sebaceous gland
activity reduces said activity, said composition consisting
essentially of: (a) a safe and effective amount of at least one
material selected from the class of histamine antagonists and
pharmaceutically-acceptable salts thereof; and (b) a
dermatological-acceptable carrier vehicle.
6. The composition of claim 5 wherein the vehicle is also
cosmetically acceptable.
7. The composition of claim 5 wherein the vehicle is also
pharmaceutically acceptable.
8. The composition of claim 5 wherein the histamine antagonist is a
histamine sub.1 receptor inhibitor and capable of inhibiting the
contraction of smooth muscle induced by the administration of
histamine or inhibiting the release of histamine by stimulated mast
cells.
9. The composition of claim 5 wherein the histamine antagonist is a
heterocyclic or a nitrogen compound having at least one benzene
ring.
10. The composition of claim 5 wherein the total amount of the
histamine antagonist compound or compounds ranges from about
0.000001 to 20% by weight relative to the total weight of the
composition.
11. The composition of claim 5 wherein the vehicle comprises an
aqueous, anhydrous, or aqueous alcoholic solution, a water-in-oil
emulsion, an oil-in-water emulsion, a microemulsion, an aqueous
gel, a hydroalcoholic gel, an anhydrous gel, a serum, a suspension
of solid particles or a dispersion of vesicles, microcapsules or
microparticles in a solid, semi-solid, liquid, or aerosol form.
12. The composition of claim 5 containing one or more additional
sebosupressive agents selected from the group consisting of a
lipase inhibitor, antiandrogens, estrogens or isoflavone estrogen
mimetics, 5-alpha reductase inhibitors, certain antifungal
compounds, e.g., 1-(1,3-Dioxolan-2-ylmethyl)-1H-imidazoles, zinc
salts, salicylate esters, benzoic acid esters, dehydroacetic acid,
ethyllinoleate, triethylcitrate, niacinamide, pygeum extract and
botanical extracts containing one or more of the aforementioned
compounds.
13. The composition of claim 5 containing at least one additional
pharmaceutically, dermatological, or cosmeceutically active
ingredients selected from the group consisting of skin lighteners
and whiteners or skin depigmenting ingredients, anti-aging
ingredients including alpha-hydroxy acids, beta-hydroxy acids,
alpha-keto acids, beta-keto acids or retinoids, antioxidants, and
skin barrier repair compounds including phytosphingosine and
ceramide compounds, essential fatty acids, proteins, hydrolyzed
proteins and amino acids.
14. The composition of claim 5 containing one or more additional
pharmaceutically or dermatological active ingredient for the
treatment or prevention of acne selected from the group consisting
of salicylic acid, lactic acid, glycolic acid, colloidal sulfur,
resorcinol, retinoic acid (tretinoin or isotretinoin), retinol,
retinaldehyde, retinyl esters, selenium disulphide, benzoyl
peroxide, azelaic acid, clindamycin, erythromycin, adapalene, and
tazarotene.
15. The composition of claim 5 containing at lease one additional
pharmaceutically or dermatological active ingredient for the
treatment or prevention of seborrhea or seborrheic dermatitis
selected from the group consisting of sulfur, resorcinol, an
alpha-hydroxy acid, a beta-hydroxy acid, ketoconazole, a steroidal
or non-steroidal anti-inflammatory, an antibiotic, coal tar or coal
tar extract, urea, selenium sulfide, and/or zinc pyrithione.
16. The composition of claim 5 wherein the carrier base or vehicle
contains at least one ingredient selected from the group consisting
of acidifying agents, alkalizing agents, aerosol propellants,
antimicrobial agents, antioxidants, buffering agents, chelating
agents, coloring agents, defoaming agents, dispersing agents,
emollients, emulsifying agents, humectants, fragrances,
moisturizers, penetration enhancers, polymers, preservatives,
suspending agents, surfactants, thickening agents and water,
alcohol, or other solvents.
Description
TECHNICAL FIELD
[0001] This invention relates to topical compositions containing
histamine antagonists and specifically H-1 antagonists, commonly
referred to as antihistamines or antihistaminics, for inhibiting
sebaceous gland activity associated with acne, seborrheic
dermatitis (seborrhea), and cosmetic oily skin conditions.
BACKGROUND OF THE INVENTION
[0002] Acne, seborrhea or seborrheic dermatitis are general classes
of skin diseases which are characterized by an abnormal function of
the sebaceous glands in human skin. Additionally, non-pathogenic
seborrhea, or, what is referred to as excessively oily skin or
cosmetic oily skin is a condition that affects a significant number
of the population and is marked by unusually high daily sebum flow,
particularly on the face.
DESCRIPTION OF THE INVENTION
[0003] In the search for a safe and effective sebossuppressive
agent that could be used topically, applicants screened a number of
classes of pharmaceuticals that are commonly in use for various
pharmacological activities, including topical antihistamines.
Antihistamine drugs or H-1 antagonists are not known to have any
effect on the sebaceous gland or the production of sebum.
[0004] Applicants have discovered that certain topical
antihistamine preparations typically sold over the counter and used
to relieve itching, in particular, diphenhydramine hydrochloride
[1-2%] and tripelennamine hydrochloride [0.5-2.0%], when used in
various formulations, can be used to reduce generation of sebum,
and moreover, once sebum is reduced, subsequent treatment of acne,
seborrhea or dermatitis by known conventional methods is more
effective and less objectionable to patients so treated.
[0005] Screening studies of candidate sebosuppressive agents,
including topical antihistamines, began with human female subjects
between the ages of 18 and 50 with a self declared history of oily
facial skin, confirmed by clinical assessment and by the use of the
Sebumeter SM 815.RTM., manufactured by Courage & Khazaka
Electronics GmbH. The Sebumeter measurement is based on grease-spot
photometry. A special tape becomes transparent in contact with the
sebum on the skin surface. For the determination of the sebum, the
measuring head of the Sebumeter cassette is inserted into the
aperture of the device, where the transparency of the tape is
measured by a light source sending light through the tape which is
reflected by a little mirror behind the tape. A photocell measures
the transparency. The light transmission represents the sebum
content on the surface of the measuring area. A microprocessor
calculates the result, which is shown on the display in .mu.g
sebum/cm.sup.2 of the skin.
[0006] Typically, qualified subjects would have a multi-year
history of problem oily skin. These subjects were asked the
question, "How long after the first washing of your face in the
morning does it take for your face to look and feel oily?" Subjects
that were cross-validated for oily skin by the Sebumeter and
clinical grading answered four hours or less to this question.
[0007] A series of pilot clinical studies evaluated the topical use
of diphenhydramine HCl at 2% in a hydoalcoholic gel formulation
shown in Exhibit 1 below
EXHIBIT 1
Oil Control Lotion
Formula #24-53A
[0008]
1 Ingredient % w/w Natrosol HHR 250 1.00 (hydroxyethylcellulose)
Camphor 0.40 Ethanol SD 40, 190 proof 50.00 Diphenhydramine HCl
(Sigma) 2.00 Phenonip (Clariant Corp.) 1.00 Deionized Water 45.60
Total 100.00
[0009] A control formulation, identical to the formula 24-53A
listed above, but without diphenhydramine, was evaluated with the
active formula among ten subjects with self-assessed oily facial
skin for a period of ten days. A randomized assignment of active
treatment or control formulation was made in this double-blind
placebo controlled pilot study. Subjects were screened for
eligibility based upon history of oily skin, agreement to use no
other topical products during the study other than the test
products and a mild facial cleansing bar provided, and answers to a
questionnaire of various inclusion and exclusion criteria. Subjects
applied the test products once a day in the morning to the forehead
and cheeks after washing the face with a mild facial cleansing
bar.
[0010] Results of this pilot study indicated moderate sebum
suppressive activity for the antihistamine gel. Self-assessment
ratings at the end of this ten day study showed a 44.2% average
reduction for the active gel (p<0.06) and 19% (p<0.03) for
the control. However, despite the large average reduction in facial
oil for the formulation with diphenhydramine HCl, variability was
high for the active gel with one subject claiming no reduction, one
subject claiming slight reduction and three subjects claiming a
drastic reduction. Sebumeter readings were taken at baseline and at
the final visit of the subjects on day 10. Sebumeter readings were
recorded for 5 facial locations for each subject, three on the
forehead and one on each cheek. The analysis of the sebumeter
readings showed a slight average reduction of roughly 10% for
either the active or control formulation. Despite the large range
in subject responses, the subject self-assessment ratings were seen
as more indicative of true sebosupressive activity versus the
Sebumeter readings for this small, short duration study.
[0011] A second pilot study evaluated the sebosuppressive activity
of diphenhydramine HCl, 2% in a silicone gel lotion containing
penetration enhancing glycols, ethanol, a silicone emulsion base
(System 3; Collaborative Laboratories), and surface-treated starch
as shown below in Exhibit 2:
EXHIBIT 2
Oil Control Lotion
Formula #24-109
[0012]
2 Ingredient % w/w Natrosol HHR 250, (1% Solution) 45.00 System
3AM-200 (Collaborative) 20.00 Methyl Sulfonyl Methane (MSM) 5.00
Dry Flo Starch (National Starch 10.00 & Chemical) Hydrolite-5
(Dragoco) 5.00 Ethanol SD 40, 190 proof 10.00 Diphenhydramine HCl
(Sigma) 2.00 Phenonip 0.30 Citrus Sea fragrance 40080T 0.07
Deionized Water 2.63 Total 100.00
[0013] Formulation 24-109 shown above was evaluated by 9 subjects
in a ten day pilot study with the study protocol similar to the
first pilot study but a second formulation without diphenhydramine
HCl was not included. Sebosuppessive activity was evaluated based
on subject self assessment at baseline and after ten days of
once/day treatment. Results of this pilot study showed an average
sebosuppression of 39.3% with a high level of significance
(p<0.007).
[0014] A third pilot study was conducted with ten subjects that
evaluated once daily application of a test formulation in the
evening after washing the face with a mild cleansing bar. The study
protocol was otherwise similar to the second pilot study. Both
Sebumeter and subject self-assessment measures were used at
baseline and at the end of the study (day 7).
[0015] The treatment prototype again contained 2% diphenhydramine
HCl in a silicone gel lotion as shown below in Exhibit 3
EXHIBIT 3
Oil Control Lotion
Formula #24-173
[0016]
3 Ingredient % w/w Natrosol HHR 250, (1% Solution) 45.00 System 3
AM-200 (Collaborative) 20.00 Ethoxydiglycol (Trivalin SF) 4.00 Dry
Flo Starch (National Starch 10.00 & Chemical) 1,3-Butylene
Glycol 4.00 Glycerin 2.00 Ethanol SD 40, 190 proof 10.00
Diphenhydramine HCl (Sigma) 2.00 Phenonip 0.60 Citrus Sea fragrance
40080T 0.07 Deionized Water 2.33 Total 100.00
[0017] Results of this third pilot study showed an average
reduction in facial oil between baseline and the 7 day readings of
23% (p<0.003) based on subject self-assessment and 15.9%
(p<0.02) based on Sebumeter readings.
[0018] Three separate pilot clinical studies demonstrated moderate
sebosuppression of facial sebum among female subjects who applied
an oil control formulation containing diphenhydramine HCl, 2%, once
daily for a period of 7-10 days.
[0019] Diphenhydramine HCl is a first generation H-1 antagonist
that has been used for over 50 years to treat cold and allergy
symptoms, motion sickness and mild insomnia. H- 1 antagonists block
histamine release from receptors present on skin and smooth muscle
tissues (e.g., capillaries within the nasal and bronchial
mucosa).
[0020] The mechanism of action for the sebosupressive activity of
diphenhydramine is unknown. However, histamine release is
presumptively involved in the production of excessively oily skin.
The total level of histamine in facial skin is relatively high when
compared with other dermal areas and significantly higher than the
histamine content of other bodily tissues or fluids with perhaps
the exception of the lungs. For example, the histamine level of
facial skin is 5 times the level of abdominal skin It is also well
known that histamine release increases the secretions from gastric,
salivary, sweat, lacrimal and bronchial glands, as well as the
pancreas.
[0021] The effect of histamine on sebaceous gland activity has not
been studied. High levels of fatty acids produced by the enzymatic
breakdown of triacylglycerols and possibly other byproducts may
initiate an irritant reaction within the sebaceous glands with
subsequent histamine release and a further increased production of
sebum as a defensive mechanism against the fatty acid/histamine
response. The cycle of fatty acid irritant->histamine
release->increased sebum production->fatty acid irritant may
be responsible for maintaining excessively oily skin throughout
much of the teenage and adult life of men and women who complain of
this problem. As stated above, diphenhydramine HCL (Benadryl.RTM.)
is a first generation H-1 antagonist. We would expect other first
generation H-1 antagonists as well as second and third generation
H-1 antagonists or combination H-1 and H-2 antagonists to have
sebosuppressive activity.
[0022] Examples of first, second and third generation
antihistamines are as follows:
First Generation H-1 Antagonists
Diphenhydramine (Benadryl.RTM.)
[0023] Chlorpheniramine
[0024] Dimenhydrinate (Dramamine.RTM.)
[0025] Brompheniramine
[0026] Promethazine
[0027] Hydroxazine (Atarax.RTM.)
[0028] Triprolidine
[0029] Trimeprazine
[0030] Cyproheptadine (Periactin.RTM.)
[0031] Phenyltoloxamine
[0032] Phenindamine
[0033] Pyrilamine
[0034] The above antihistamines are listed as the base compound but
may typically be used as a salt (e.g., diphenhydramine
hydrochloride, chlorpheniramine maleate, pyrilamine tannate,
hydroxazine pamoate, etc.). First generation or so-called classic
antihistamines generally fall into one of six chemical classes:
Alkylamines, Ethanolamines, Ethylenediamines, Piperazines,
Phenothiazines, or Piperadines.
Second Generation H-1 Antagonists ("Non-Sedating
Antihistamines")
[0035] Terfenadine (Seldane.RTM.)
[0036] Fexofenadine(Allegra.RTM.)
[0037] Loratadine(Claritin.RTM.)
[0038] Cetirizine (Zyrtec.RTM.)
[0039] Clemastine (Tavist.RTM.)
[0040] Disloratidine (Clarinex.RTM.)
[0041] Ranitidine
[0042] The second generation antihistamines are listed as base
compounds but some may be used as a salt (e.g. Cetirizine HCl)
Third Generation H-1 And Combination Antagonists
[0043] tecastemizole
[0044] levocetirizine
[0045] Azelastine (Astelin(.RTM.)
[0046] Astimazole
[0047] H-1/NK-1 dual antagonists
[0048] Doxepin HCL (Zonalon.RTM.)
[0049] The above H-1 antagonists are listed for illustration
purposes and are not inclusive of all antihistamine compounds which
are typically heterocyclic or nitrogen compounds having at least
one benzene ring and further characterized by inhibiting the
contraction of smooth muscles induced by the administration of
histamine or inhibiting the release of histamine by stimulated mast
cells.
[0050] Other histamine antagonists that preferentially block
histamine release from gastric parietal cells, known as H-2
inhibitors (e.g.,Pepcid.RTM., Tagamet.RTM., Zantac(.RTM.) or block
histamine release from neurons and are known as H-3 inhibitors
(e.g., desferriozamine, denbufylline, donepezil) are specific for
gastric or neuron receptor cells, respectively. However, H-1, H-2,
and H-3 receptors are present in the skin and recent studies have
shown that both H-1 and H-2 antagonists improve the skin's barrier
repair properties and prevent epidermal hyperplasia induced by
barrier disruption. H-3 antagonists had no effect on barrier
repair.
[0051] In order to confirm that H-1 antagonists, as a class have
sebosuppresssive activity rather than a specific sebosuppressive
activity only for diphenhydramine HCl, a fourth pilot clinical was
conducted with a topical formulation containing tripelennamine
hydrochloride, a first generation antihistamine classified as a
non-specific histamine antagonist with low to no anticholinergic
activity. Tripelennamine has a long history of topical and systemic
use and is currently approved for OTC topical use in the U.S. at
concentrations of 0.5-2%.
[0052] The fourth pilot clinical study evaluated the twice daily
(morning and evening) topical application of a lotion formulation
containing tripelennamine HCl, 2% versus a control lotion with no
antihistamine as shown in Exhibits 4 and 5 below. A randomized
assignment of active treatment or control formulation was made in
this double-blind placebo controlled pilot study. Subjects were
screened for eligibility based upon history of oily skin associated
with mild-moderate acne, agreement to use no other topical products
during the study other than the test products and a mild facial
cleansing bar provided, as well as answers to a questionnaire of
various inclusion and exclusion criteria. A total of 15 subjects
(8-test product; 7-control product) treated their facial skin twice
daily for 29 days. The subjects assessed the degree of facial
oiliness daily on an eight point analog scale utilizing a
self-assessment criterion described above for the other pilot
studies. Each subject recorded the degree of oily skin on a daily
log and the daily score was compared to the original baseline score
to calculate the % reduction in oil. For example, if subject 1, on
day 4 had a self-assessment score of 2.0 and a baseline score of
1.0, the % reduction is calculated as the treatment score minus the
baseline score divided by the baseline score. In this example, the
% reduction=4.0-2.0/2.0.times.100=100% reduction.
EXHIBIT 4
Oil Control Lotion
Formula #25-147
[0053]
4 Ingredient % w/w Natrosol HHR 250, (1% Solution) 45.00 System 3
AM-200 (Collaborative) 20.00 Ethoxydiglycol (Trivalin SF) 4.00
1,3-Butylene Glycol 4.00 Glycerin 2.00 Ethanol SD 40, 190 proof
10.00 Tripelennamine HCl (Sigma) 2.00 Phenonip 0.60 Citrus Sea
fragrance 40080T 0.07 Deionized Water 12.33 Total 100.00
EXHIBIT 5
Oil Control Lotion
Formula #25-155
[0054]
5 Ingredient % w/w Natrosol HHR 250, (1% Solution) 45.00 System 3
AM-200 (Collaborative) 20.00 Ethoxydiglycol (Trivalin SF) 4.00
1,3-Butylene Glycol 4.00 Glycerin 2.00 Ethanol SD 40, 190 proof
10.00 Phenonip 0.60 Citrus Sea fragrance 40080T 0.07 Deionized
Water 14.33 Total 100.00
[0055] Results of this fourth pilot clinical showed a statistically
significant reduction in facial oil for the test product containing
tripelennamine HCl beginning on day 4 (p=0.0303) and every day from
day 4 through the end of the study on day 29 (p=0.0008) with mean
daily oil reduction ranging from 58.3% to 140.4% compared to the
baseline. Subjects in the control group rated their treatment as
having a positive affect on oil production as well but the average
daily reduction was much lower for the control ranging from zero to
125% compared to baseline and the sebosuppression was inconsistent
throughout the study with nearly half the days showing no
statistically significant reductions. A comparison of the mean
sebum reductions by day for 29 days for the topical antihistamine
formula (Formula #25-147; Treatment A) versus the control
formulation (Formula .andgate.25-155; Treatment B) is shown in
Exhibits 6 & 7 below:
EXHIBIT 6
[0056]
6 Average percent change from baseline TRT = A VISIT N obs N Mean 1
8 8 58.3333333 2 8 8 108.3333333 3 8 8 99.5833333 4 8 8 93.7500000
5 8 8 93.7500000 6 8 8 104.5833333 7 8 8 87.9166667 8 8 8
92.0833333 9 8 8 127.9166667 10 8 8 134.1666667 11 8 8 121.6666667
12 8 8 100.8333333 13 8 8 120.0000000 14 8 8 124.1666667 15 8 8
161.6666667 16 8 8 121.6666667 17 8 8 125.8333333 18 8 8
109.1666667 19 8 8 123.3333333 20 8 8 119.1666667 21 8 7
112.3809524 22 8 8 100.8333333 23 8 7 115.2380952 24 8 8
121.6666667 25 8 8 127.9166667 26 8 8 115.4166667 27 8 8
115.4166667 28 8 8 140.4166667 29 8 8 140.4166667
EXHIBIT 7
[0057]
7 Average percent change from baseline TRT = B VISIT N Obs N Mean 1
7 7 1.7857143 2 7 7 0 3 7 7 11.9047619 4 7 7 15.2777778 5 7 7
26.1904762 6 7 7 27.7777778 7 7 7 29.7619048 8 7 7 47.6190476 9 7 7
42.4603175 10 7 7 38.0952381 11 7 7 38.0952381 12 7 7 54.3650794 13
7 7 55.9523810 14 7 7 55.9523810 15 7 7 59.1269841 16 7 7
55.9523810 17 7 7 57.5396825 18 7 7 72.0238095 19 7 7 70.2380952 20
7 7 54.3650794 21 7 7 62.6984127 22 7 7 64.2857143 23 7 7
64.2857143 24 7 7 80.1587302 25 7 7 65.8730159 26 7 7 60.7142857 27
7 7 76.7857143 28 7 7 73.2142857 29 7 4 125.0000000
[0058] A statistical analysis of the total data for all subjects
for all of the 29 days of active treatment (A) versus control
treatment (B) using an ANOVA model shows that there is a highly
significant overall effect due to the active treatment (A) vs.
control (p<0.0001), with and an increased overall sebosupressive
effect over time (p<0.02; Day 1 to Day 29), with no interaction
effect between treatment and time.
[0059] Moreovr, a questionnaire administered to the subjects at the
end of the study indicated substantial oil control activity for the
product containing the antihistamine but not for the control.
[0060] For example, at the conclusion of the study, 7 of 8 subjects
treated with the antihistamine lotion rated their skin as less oily
from daily use of the lotion while only 3 of 7 subjects that used
the control rated their skin as less oily. The results of this
study and the previous three studies summarized above clearly
demonstrate that histamine antagonists and specifically, H-1
receptor antagonists have the ability to reduce, suppress, control
and or prevent the production of sebum when topically applied to
subjects suffering from oily facial skin and oily skin associated
with acne.
[0061] In order to determine if the sebosupressive activity of
topically applied H-1 antagonists have synergistic or additive
activity when combined with acne treatments, a topical formulation
containing both diphenhydramine HCl, 2% and salicylic acid, 2% was
evaluated on acne patients with moderately oily facial skin. The
formulas for this acne and oil control treatment gel as well as the
positive control formula containing the same acne active and base,
but no H-1 antagonist, are shown in Exhibit 8 and Exhibit 9
below.
EXHIBIT 8
Acne/Oil Control Lotion
Formula #26-79 A
[0062]
8 Ingredient % w/w Diphenhydramine Hydrochloride 2.00 Salicylic
Acid 2.00 Natrosol HHR 250, (1% Solution) 45.00 Ethoxydiglycol
(Trivalin SF) 6.00 1,3-Butylene Glycol 6.00 Glycerin 2.00 Ethanol
SD 40, 190 proof 20.00 Glucam E-20 (Amerchol) 2.00 Phenonip 0.60
Citrus Sea fragrance 40080T 0.07 Disodium EDTA 0.05 Deionized Water
14.28 Total 100.00
EXHIBIT 9
Acne/Oil Control Lotion
Formula #26-79 B
[0063] (Positive Control))
9 Ingredient % w/w Salicylic Acid 2.00 Natrosol HHR 250, (1%
Solution) 45.00 Ethoxydiglycol (Trivalin SF) 6.00 1,3-Butylene
Glycol 6.00 Glycerin 2.00 Ethanol SD 40, 190 proof 20.00 Glucam
E-20 (Amerchol) 2.00 Phenonip 0.60 Citrus Sea fragrance 40080T 0.07
Disodium EDTA 0.05 Deionized Water 16.28 Total 100.00
[0064] The fifth pilot clinical study evaluated twice daily
(morning and evening) topical facial application of a clear
lotion/gel formulation containing diphenhydramine HCl, 2% and
salicylic acid, 2% (Formula A; Exhibit 8) versus a positive control
lotion/gel with no antihistamine and 2% salicylic acid (Formula B;
Exhibit 9). A randomized assignment of formulation A or B was made
in this double-blind, positive control pilot study. Subjects were
screened for eligibility based upon history of oily skin associated
with mild-moderate acne, agreement to use no other topical products
during the study other than the test products and a mild facial
cleansing bar provided, as well as answers to a questionnaire of
various inclusion and exclusion criteria. A total of 18 subjects
(9-test product; 9-control product) treated their facial skin twice
daily for 8 weeks. Subjects were graded for acne (papules, nodules,
pustules, closed and open comedones, etc.) on the cheek, chin and
forehead area by a trained clinician and facial oiliness was
measured by the test subjects utilizing the self-assessment
criteria described above for the other clinical studies as well as
by the clinician.
[0065] At the end of 4 weeks, subjects treated with either the
combined active treatment (Formula A) or the positive control
treatment (Formula B) showed approximately 40% reduction in acne
papules (p<0.01). However, only Formula A, containing both the
histamine antagonist and salicylic acid, showed a statistically
significant and meaningful reduction in facial oiliness (25.6%
average reduction; p<0.004) based on the clinician assessment (4
weeks compared to baseline). Additionally, the patient
self-assessment diary data showed increased sebosuppressive
activity over time with average reductions of 8.3%, 41.7% &
44.4% for weeks two, three, and four of the study (p=0.22) while
the control formulation showed reductions of 2.8%, 13.2%, &
8.9% for these same time intervals.
[0066] The series of five clinical studies outlined above show a
consistent pattern of sebosuppressive activity for the topical
application of histamine antagonists when applied to excessively
oily skin, whether associated with disease (e.g., acne) or
cosmetically oily facial skin.
[0067] Seborrhea or seborrheic dermatitis is another skin disease
thought to be associated with abnormal function of the sebaceous
glands. It occurs in areas where there are large numbers of
sebaceous glands and is characterized by flaking of the skin and
red, mildly inflammatory patches. Seborrhea is most common in the
hair (a form of dandruff), scalp margins, eyebrows, naso-labial
folds, external ear canals, posterior auricular fold, and prestemal
area.
[0068] Several subjects with bilateral seborrheic dermatitis of the
eyebrows, naso-labial folds and posterior auricular folds were
treated with Formula A (Exhibit 8) on one side of the face and
Formula B (Exhibit 9) on the other side of the face for up to two
weeks. Clinical observations of the subjects thus treated indicated
superior efficacy for the treatment containing a histamine
antagonist (Formula A) based on clinical assessment of the
comparative reduction in scaling and erythema.
Ancillary Actives
[0069] The compositions of the present invention can further
comprise one or more ancillary active ingredients capable of
functioning via a different mode of action in order to enhance the
sebosupressive activity of the histamine antagonist(s) and/or to
provide other benefits. These ancillary actives may be combined
with the histamine antagonist in a suitable dermatological or
cosmetic carrier to 1) further reduce the oily or shiny appearance
of skin, 2) provide anti-acne benefits to complement the
sebosupressive activity of the histamine antagonist, and 3) provide
additional benefits beyond the histamine antagonist effect in the
treatment of seborrheic dermatitis, or provide additional cosmetic
benefits to facial skin, as follows:
[0070] A. Oil Control Agents
[0071] The ancillary oil control agents may include materials that
absorb sebum on the skin surface, materials that reduce sebum
spreadability, and/or sebosupressive agents that are complementary
to the sebosupressive effect of the histamine antagonist(s).
Nonlimiting examples of sebum absorbing materials are clays (e.g.,
bentonite), talcs, silicas, starches, oil-absorbing polymers (e.g.,
Microsponge.RTM. and Polytrap.RTM. polymers produced by Advanced
Polymer Systems). Nonlimiting examples of agents that reduce the
spreadability of sebum may include hydroxysultaine compositions
described in U.S. Pat. No. 4,534,964; in U.S. Pat. No. 4,529,588,
and silicone polymers described in U.S. Pat. No.4,515,784.
[0072] Nonlimiting examples of ancillary sebosupressive agents are
niacinamide, lipase inhibitors, antiandrogens, estrogens or
isoflavone estrogen mimetics, 5-alpha reductase inhibitors, certain
antifungal compounds, e.g.,
1-(1,3-Dioxolan-2-ylmethyl)-1H-imidazoles, zinc salts, salicylate
esters, benzoic acid esters, dehydroacetic acid and salts thereof,
ethyllinoleate, triethylcitrate, pygeum extract and botanical
extracts containing one or more of the aforementioned compounds as
described in the article on "Sebosupression", Cosmetics &
Toiletries, vol. 102, pp.140-146 (April 1987).
[0073] B. Anti-Acne Agents
[0074] Compositions of the present invention can be used to treat
acne by reducing, preventing or arresting the acne process and/or
clearing or healing existing lesions and can contain ancillary
anti-acne active(s) selected from antimicrobial agents,
antiandrogens, and comedolytic/keratolytic agents.
[0075] Nonlimiting examples of comedolytic and keratolytic agents
useful in the present invention are selected from the group of
salicylic acid, resorcinol, sulfur, retinoids, lactic acid and
glycolic acid. Retinoids includes retinoic acid (all-trans retinoic
acid and/or 1 3-cis-retinoic acid), retinal, retinol, and retinyl
esters. Nonlimiting examples of antimicrobial agents includes
benzoyl peroxide, erythromycin, tetracycline, clindamycin, azelaic
acid, adapalene, and tazarotene. Nonlimiting examples of
antiandrogens include cyproterone acetate, drospirenone,
spironolactone, dienoestrol diacetate and flutamide.
[0076] C. Seborrheic Dermatitis Actives
[0077] Compositions of the present invention can be used to treat
seborrheic dermatitis by reducing or inhibiting the underlying
sebaceous activity to help reduce or eliminate the seborrhea
plaques which are characterized by scaling and inflammation.
Treatment compositions of this invention can contain ancillary
active ingredients that assist in reducing the scaling via a
keratolytic effect, by reducing inflammation by steroidal or
non-steroidal anti-inflammatory activity, by
antimicrobial/anti-dandruff activity or by some combination of
these effects.
[0078] Nonlimiting examples of ancillary actives include coal tar
and coal tar extracts, sulfur, resorcinol, salicylic acid, lactic
acid, glycolic acid and other keratolytic alpha-hydroxy and
beta-hydroxy acids; ketoconazole, selenium sulfide, zinc pyrithione
and other antimicrobials active against Pityrosporum sp.; steroidal
anti-inflammatory agents, e.g., corticosteroids such as
hydrocortisone, clobetasol valerate, dexamethasone, triamcinolone
acetonide, betamethasone and non-steroidal anti-inflammatory
agents, e.g., piroxicam, fendosal, diclofenac, flufenamic acid,
naproxen, ibuprofen, and phenylbutazone.
[0079] D. Other Actives
[0080] Compositions of the present invention are useful for
reducing, inhibiting or eliminating sebum and the negative effect
of sebum on the skin. Oily skin, even when not associated with acne
or seborrhea, is a particular problem for individuals afflicted
with oily facial skin. Accumulation of oil on the face leads to a
shiny appearance and the feeling of greasy, unclean skin. This
necessitates, frequent washing and attempts throughout the day to
keep the facial skin clean.
[0081] Compositions of the present invention when applied to facial
skin greatly diminish or even eliminate the cosmetic problems
associated with oily facial skin.
[0082] It is expected that ancillary actives or additives could be
added to the composition of the present invention for treatment of
other cosmetic facial problems in addition to oily skin. For
example, individuals with excessively oily skin or combination skin
that includes areas of facial skin that are oily and other areas
that are normal or dry, may also have facial photodamage and other
signs of skin aging that may include fine lines and wrinkles, age
spots and uneven skin pigmentation, rough or uneven skin surface
texture, and areas of dryness or blotchiness. Therefore,
nonlimiting examples of other cosmetic additives may include skin
whiteners or lighteners, e.g., kojic acid, arbutin, ascorbic acid
and ascorbate salts; anti-aging ingredients such as alpha-hydroxy
acids, beta-hydroxy acids, alpha-keto acids, beta-keto acids, e.g.,
lactic acid, glycolic acid, and retinoids, e.g., tretinoin, retinal
acetate, retinol; antioxidants, e.g., tocopherol, tea polyphenols,
alpha bisabolol; and skin barrier repair ingredients, e.g.,
sphingosine, phytosphingosine and other pro-ceramide and ceramide
compounds, linoleic acid or other essential fatty acids, proteins,
hydrolyzed proteins, and amino acids.
Dermatologically & Cosmeticly Acceptable Carriers Or
Vehicles
[0083] The carrier vehicle for the present invention is designed to
deliver the histamine antagonist and any ancillary active into the
skin at the appropriate concentration. The carrier can act as a
diluent, solvent, dispersant, penetrant or the like for the
histamine antagonist and the ancillary active(s) to ensure that the
composition can be applied and distributed evenly over the areas of
sebaceous activity at an appropriate concentration.
[0084] Suitable carriers include conventional or otherwise known
carriers that are cosmetically and dermatological acceptable and
are physically and chemically compatible with the active
components. The carrier vehicle of the present invention includes a
wide variety of product forms that are known in the art.
[0085] The carrier vehicle may comprise an aqueous, anhydrous, or
aqueous alcoholic solution, a water-in-oil emulsion, an
oil-in-water emulsion, a microemulsion, an aqueous gel, a
hydroalcoholic gel, an anhydrous gel, a serum, a suspension of
solid particles or a dispersion of vesicles, microcapsules or
microparticles. The carrier vehicle may be a solid, semisolid,
liquid, or aerosol composition.
[0086] The carrier vehicle may contain one or more ingredients
selected from the group consisting of acidifying agents, alkalizing
agents, aerosol propellants, antimicrobial agents, antioxidants,
buffering agents, chelating agents, coloring agents, defoaming
agents, dispersing agents, emollients, emulsifying agents,
humectants, fragrances, moisturizers, penetration enhancers,
polymers, preservatives, suspending agents, surfactants, thickening
agents and water, alcohol, or other solvents.
[0087] While the examples set forth above illustrate specific
embodiments of the invention and are considered non-limiting
examples with variations and modifications thereof all being within
the spirit and purview of this invention.
* * * * *